Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE‐deficient mice

Abstract

The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the development of atherosclerosis, we used apoE-deficient mice with a macrophage-restricted deletion of Rb (Rb(del) mice) and control littermates (Rb(fl) mice). After 12 wk feeding a cholesterol-rich diet, the Rb(del) mice showed a 51% increase in atherosclerotic lesion area with a 39% increase in the relative number of advanced lesions. Atherosclerotic lesions showed a 13% decrease in relative macrophage area and a 46% increase in relative smooth muscle cell area, reflecting the more advanced state of the lesions. The increase in atherosclerosis was independent of in vitro macrophage modified lipoprotein uptake or cytokine production. Whereas macrophage-restricted Rb deletion did not affect lesional macrophage apoptosis, a clear 2.6-fold increase in lesional macrophage proliferation was observed. These studies demonstrate that macrophage Rb is a suppressing factor in the progression of atherosclerosis by reducing macrophage proliferation.

Local proliferation dominates lesional macrophage accumulation in atherosclerosis

“…6 c–e). These data are consistent with studies in which genetic disruption of tumor suppressor genes and cell cycle regulators promoted macrophage proliferation and increased atherosclerosis 34,35 . These findings demonstrate that cellular proliferation is a dominant feature of atherosclerotic development and a potent therapeutic target.…”

p19ARFDeficiency Reduces Macrophage and Vascular Smooth Muscle Cell Apoptosis and Aggravates Atherosclerosis

“…Indeed, atheroma progression is affected in mice with altered expression of several tumor suppressors that modulate cell proliferation and apoptosis. Unlike p21 Cip1 , whose genetic ablation unexpectedly protects from atherosclerosis in apoE-null mice (33,34), the absence of p53 (35)(36)(37)(38), p27 Kip1 (39,40), and retinoblastoma (41) proteins aggravates atherosclerosis in different murine models (apoE-null, LDL receptor-null, and apoE*3-Leiden transgenic mice). Excessive proliferation of macrophages and VSMCs has been suggested as a mechanism contributing to the acceleration of atherosclerosis in mice lacking p27 Kip1 , retinoblastoma, and p53.…”

Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs?

“…of Pages 9 may protect against atherosclerosis by controlling macrophage proliferation. Mice lacking the Retinoblastoma protein (pRB), whose activity is controlled by p16 INK4a and p15 INK4b [14], in macrophages, have larger plaques associated with increased macrophage proliferation [42,43]. Likewise, either whole body- [44] or bone marrow-deficiency [45] of the CDKI p27 kip1 increases cellular proliferation and aggravates atherosclerosis in ApoE-deficient animals.…”